Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Development of an amphicrine pancreas-on-a-chip to study tumor initiation in a diabetic microenvironment

International audienceIn 2021, 537 million of the global adult population worldwide were living with diabetes [1]. Type 2 diabetes, which accounts for more than 95% of diabetes mellitus, is associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC) [2]. PDAC is a destructive disease with an unoptimistic prognosis. It ranks 9 th in the incidence of solid cancers but 4 th for cancerrelated deaths [3]. While several studies described potential molecular links between diabetes mellitus and PDAC, there is a lack of pertinent biological models to better elucidate the molecular mechanisms involved [2]. Three-dimensional cell cultures emerge as more relevant models towards organ-emulating constructs superseding the traditional two-dimensional format. Here, we created a perfusable microtissue-laden device using 3D printing technology to investigate the molecular links between diabetic microenvironment and PDAC initiation. Methods We use a 3D-printed device in which fugitive ink has been extruded to form a pancreatic duct. The duct is lined with a hydrogel from healthy or diabetic origin that also contain islets of Langerhans. The duct-mimicking channel is then filled with human pancreatic epithelial cells either healthy or harboring preneoplastic abnormalities. Results We developed an amphicrine pancreas-on-a-chip model that recapitulate diabetic condition and allow immunostaining labelling in 3D, as confirmed by ELISA quantification of insulin secretion in response to glucose stimulation, and light-sheet microscopy. We have also developed a decellularized extracellular matrix of healthy tissue that allows perfusion and good cell survival, a necessary first step towards the preparation of matrix from diabetic tissue. We maintain the perfused devices over several weeks, enabling the study of tumor initiation over long periods. We will further analyze the link between the diabetic environment and the cell activity (proliferation, migration) in cells harboring preneoplastic abnormalities (such as genetic mutations, inflammatory/hyperglycemia exposition) to study the link between cells abnormalities in diabetic patients and the risk for development of pancreatic cancer. Conclusion and significance Our approach allows the fabrication of semi-automatized and standardized devices that can be used for multiple organ models. The advantages of hydrogel-based devices are the possibility of cell self-arrangement in the relatively large bulk of hydrogel. The self-organized cells will then synthesize their own extracellular matrix, and will mature over time. The results are promising to generate glucose-responsive, functional Langerhans islet-based device for a breakthrough research in the early stages of pancreatic adenocarcinoma in diabetic patients, to identify new early diagnostic biomarkers

Development of an amphicrine pancreas-on-a-chip to study tumor initiation in a diabetic microenvironment

International audienceIn 2021, 537 million of the global adult population worldwide were living with diabetes [1]. Type 2 diabetes, which accounts for more than 95% of diabetes mellitus, is associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC) [2]. PDAC is a destructive disease with an unoptimistic prognosis. It ranks 9 th in the incidence of solid cancers but 4 th for cancerrelated deaths [3]. While several studies described potential molecular links between diabetes mellitus and PDAC, there is a lack of pertinent biological models to better elucidate the molecular mechanisms involved [2]. Three-dimensional cell cultures emerge as more relevant models towards organ-emulating constructs superseding the traditional two-dimensional format. Here, we created a perfusable microtissue-laden device using 3D printing technology to investigate the molecular links between diabetic microenvironment and PDAC initiation. Methods We use a 3D-printed device in which fugitive ink has been extruded to form a pancreatic duct. The duct is lined with a hydrogel from healthy or diabetic origin that also contain islets of Langerhans. The duct-mimicking channel is then filled with human pancreatic epithelial cells either healthy or harboring preneoplastic abnormalities. Results We developed an amphicrine pancreas-on-a-chip model that recapitulate diabetic condition and allow immunostaining labelling in 3D, as confirmed by ELISA quantification of insulin secretion in response to glucose stimulation, and light-sheet microscopy. We have also developed a decellularized extracellular matrix of healthy tissue that allows perfusion and good cell survival, a necessary first step towards the preparation of matrix from diabetic tissue. We maintain the perfused devices over several weeks, enabling the study of tumor initiation over long periods. We will further analyze the link between the diabetic environment and the cell activity (proliferation, migration) in cells harboring preneoplastic abnormalities (such as genetic mutations, inflammatory/hyperglycemia exposition) to study the link between cells abnormalities in diabetic patients and the risk for development of pancreatic cancer. Conclusion and significance Our approach allows the fabrication of semi-automatized and standardized devices that can be used for multiple organ models. The advantages of hydrogel-based devices are the possibility of cell self-arrangement in the relatively large bulk of hydrogel. The self-organized cells will then synthesize their own extracellular matrix, and will mature over time. The results are promising to generate glucose-responsive, functional Langerhans islet-based device for a breakthrough research in the early stages of pancreatic adenocarcinoma in diabetic patients, to identify new early diagnostic biomarkers

Evaluation of the non-steroidal anti-inflammatory drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, randomized, double-blind, placebo-controlled SPARSE study

International audienceIntroductionIn clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly discontinued after response to biologic therapy is achieved in patients with axial spondyloarthritis (axSpA), but the impact of NSAID discontinuation has not been assessed in prospective controlled trials. The aim of the SPARSE study was to evaluate the effects of the anti-tumor necrosis factor agent etanercept on NSAID intake and conventional clinical outcomes in axSpA patients.MethodsIn the double-blind, placebo-controlled period, patients with active (mini Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4) axSpA despite optimal NSAID intake were randomized to receive etanercept 50 mg or placebo once weekly for 8 weeks. All patients were advised to taper/discontinue their NSAID intake during the treatment period. NSAID intake was self-reported by diary and Assessment of SpondyloArthritis International Society (ASAS)-NSAID scores calculated based on ASAS recommendations. The primary endpoint was change from baseline to week 8 in ASAS-NSAID score (analysis of covariance).ResultsIn 90 randomized patients at baseline, mean age (standard deviation) was 38.9 (11.8) years; disease duration, 5.7 (8.1) years; 59/90 (66%) were human leukocyte antigen-B27 positive; 51/90 (57%) had radiographic sacroiliitis; and 45/90 (50%) were magnetic resonance imaging sacroiliitis-positive. Mean ASAS-NSAID scores were similar between etanercept and placebo groups at baseline (98.2 (39.0) versus 93.0 (23.4)), as were BASDAI (6.0 (1.7) versus 5.9 (1.5)), and Bath Ankylosing Spondylitis Functional Index (5.2 (2.1) versus 5.1 (2.2)). Mean changes (SE) in ASAS-NSAID score from baseline to week 8 were –63.9 (6.1) and –36.6 (5.9) in the etanercept and placebo groups (between-group difference, –27.3; P = 0.002). Significantly higher proportions of patients receiving etanercept versus placebo had an ASAS-NSAID score <10 (46% versus 17%; P = 0.008) and ASAS-NSAID score of 0 (41% versus 14%; P = 0.013) at this time point. Significantly more patients in the etanercept versus placebo group achieved BASDAI50 (39% versus 18%; P = 0.032) and ASAS40 (44% versus 21%; P = 0.028) at week 8.ConclusionsIn patients with axSpA, etanercept was associated with clinically relevant NSAID-sparing effects in addition to significant improvements in conventional clinical outcomes

Characterizing biomarkers for early diagnosis of pancreatic cancer

International audienc

Characterizing biomarkers for early diagnosis of pancreatic cancer

International audienc

Elementos para uma história da neuroascese Elements for a history of neuroascese

O espetacular progresso das neurociências e o intenso processo de popularização, via mídia, de imagens e informações que associam a atividade cerebral a praticamente todos os aspectos da vida produzem, no imaginário social, crescente percepção do cérebro como detentor das propriedades e autor das ações que definem o que é ser alguém. Nesse contexto sociocultural, aumenta o interesse pela neuroascese, isto é, discursos e práticas a respeito de como agir sobre o cérebro para maximizar sua performance. Com o objetivo de traçar alguns elementos da história da ascese cerebral, resgatam-se momentos históricos do século XIX em que práticas neuroascéticas eram comuns. O artigo problematiza a continuidade dessas práticas na atualidade, levando em conta os diferentes contextos socioculturais e históricos nos quais se originam.<br>The spectacular progress of the neurosciences, as well as the intense process of popularization by the media of images and information that associate cerebral activity with practically every aspect of life, have produced a growing perception of the brain as the site and agent of all the properties and actions that define us as human beings. Today's socio-cultural context has seen increased interest in 'neuroascese', that is, discourses and practices aimed at maximizing brain performance. Tracing elements of the history of 'brain ascese' back to historical moments of the nineteenth century in which neuroascetic practices were commonplace, the article examines their continued use today, taking into account the social, cultural, and historical contexts in which they originated